The presence of growth hormone receptor/binding protein (GHR/BP) has been reported in both the juvenile (Lobie et al (1993)) and adult (Burton et al (1992)) rat brains, and its pattern of distribution appears to be widespread, especially in the juvenile CNS. The ontogeny of expression of the GHR/BP also appears to be similar to IGF-1 and the IGF-1 receptor expression in the developing CNS, being produced mainly in fetal and early post-natal life and declining thereafter (Bartlett et al (1991), Bondy and Lee (1993), Garofalo et al (1989)). Studies of transgenic mice have showed that both IGF-1 knockout and growth hormone deficient mice exhibit hypomyelinated, microcephalic brains (Beck et al (1995), Noguchi (1991)), thus indicating a role for both growth hormone and IGF-1 in brain growth, development and myelination. A recent study in growth hormone-deficient children has shown a striking correlation between hypothalamic disturbances influencing growth hormone secretion and their relative score in a visual motor psychological test, indicating a link between an abnormal somatotropic axis and reduced cognitive performance (Andronikof-Sanglade et al (1997)).
There has however to date been no demonstration of a neuroprotective function for growth hormone. (By “neuroprotective” is meant exhibiting neuroprophylactic and/or neuronal rescue capabilities in the CNS). While U.S. Pat. No. 4,791,099 does describe the symptoms of central nervous system diseases as being treatable with a combination of growth hormone and androgens, there is no teaching of administering growth hormone alone. Certainly, there is no teaching in U.S. Pat. No. 4,791,099 of growth hormone as having other than an anabolic effect to render patients treated more receptive to the restorative effects of the androgens. No neuroprophylactic or neuronal rescue capabilities are suggested.
It is the applicant's finding that growth hormone is itself neuroprotective. This finding is surprising in spite of the somatotropic axis relationship between growth hormone and IGF-1 and the demonstration that IGF-1 has neuronal rescue capabilities, both in vitro and in vivo (see Knusel et al (1990), Guan et al (1993)). That is because IGF-1 acts through the IGF-1 receptor whereas growth hormone does not. Thus, growth hormone is neuroprotective in the thalamus, where there is reported distribution of growth hormone receptor immunoreactivity (Lobie et al (1993) Developmental Brain Research 74: 225) but not in the striatum, whereas IGF-1 is neuroprotective in the striatum, where IGF-1 receptors have been reported to be present (Hill et al (1986) Neuroscience 17:1127; Lesinak et al (1988) Endocrinology 123:2089)) but not in the thalamus. Furthermore and as the applicants have found that growth hormone administered centrally to the brain is neuroprotective without effecting a concurrent increase in IGF-1 levels.
It is these surprising findings upon which the present invention is based.